Dual-Acting Cholinesterase-Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo.
Dual-Acting Cholinesterase-Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo.
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DOI：
10.1021/acs.jmedchem.9b00623
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发表时间：
2019-10-24
影响因子：
7.3
通讯作者：
Decker M
中科院分区：
文献类型：
--
作者：
Scheiner M;Dolles D;Gunesch S;Hoffmann M;Nabissi M;Marinelli O;Naldi M;Bartolini M;Petralla S;Poeta E;Monti B;Falkeis C;Vieth M;Hübner H;Gmeiner P;Maitra R;Maurice T;Decker M
我们已经设计并合成了一系列的14个混合分子的胆碱酯酶（ChE）抑制剂他克林和苯并咪唑为基础的人类大麻素受体亚型2（hCB 2 R）激动剂，并在体外和体内研究它们。这些化合物是有效的胆碱酯酶抑制剂，并且对于最有希望的杂合体，评估了人乙酰胆碱酯酶（hAChE）抑制的机制以及它们干扰AChE诱导的β-淀粉样蛋白（Aβ）聚集和Aβ自聚集的能力。评价所有杂交体对hCB 1 R和hCB 2 R的亲和力和选择性。为了确保杂交体保留其激动剂特征，定量cAMP调节基因的表达，并测定效力和功效。此外，研究了杂交体对小胶质细胞活化和对HT-22细胞的神经保护作用的影响。最有希望的体外杂交体在阿尔茨海默氏症小鼠模型中以低剂量（0.1 mg/kg，i. p.）显示出明显的神经保护作用，即使在高剂量（3 mg/kg，i. p.）下也没有肝毒性。
We have designed and synthesized a series of 14 hybrid molecules out of the cholinesterase (ChE) inhibitor tacrine and a benzimidazole-based human cannabinoid receptor subtype 2 (hCB2R) agonist and investigated them in vitro and in vivo. The compounds are potent ChE inhibitors, and for the most promising hybrids, the mechanism of human acetylcholinesterase (hAChE) inhibition as well as their ability to interfere with AChE-induced aggregation of β-amyloid (Aβ), and Aβ self-aggregation was assessed. All hybrids were evaluated for affinity and selectivity for hCB1R and hCB2R To ensure that the hybrids retained their agonist character, the expression of cAMP-regulated genes was quantified, and potency and efficacy were determined. Additionally, the effects of the hybrids on microglia activation and neuroprotection on HT-22 cells were investigated. The most promising in vitro hybrids showed pronounced neuroprotection in an Alzheimer’s mouse model at low dosage (0.1 mg/kg, i.p.), lacking hepatotoxicity even at high dose (3 mg/kg, i.p.).
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影响因子：
5.8
作者：
ELLMAN, GL;COURTNEY, KD;FEATHERSTONE, RM
通讯作者：
FEATHERSTONE, RM
影响因子：
3.4
作者：
Dolles, Dominik;Nimczick, Martin;Decker, Michael
通讯作者：
Decker, Michael
DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
影响因子：
3.5
作者：
Fulp, Alan;Zhang, Yanan;Maitra, Rangan
通讯作者：
Maitra, Rangan
影响因子：
4
作者：
Giacobini, E
通讯作者：
Giacobini, E